1-thiocarbamyl-4-heterocyclic piperazines



min -l Patented Jan. 12, 1954 UNITED STATES PATENT OFFICE l-THiOCARBAMYL-hHETEROCYCLIG PIPERAZINES- Edward A. Conroy, Plainfield;N; J., assi'g'nor to American Gyanamid Company, New York, N Ya,a-corporationof Maine Nb Drawing. Application October 27,1952,

Serial No. 317,150

7*Claims. (Cl.260-256.5)

1 950,-nowabandoned.

More-specificallyathe present invention is concerned With compoundscapable of representation by the generic formula:

"razinyfor' thiazolyl'radical and grand 112represetifliydro'genprmethyl; R1 represents hydrogen"oranaliphaticradical"of L 6 carbon atoms; and nl-representsnydmgen, analkylra'dical of 1-6 "carbon atomsoi'fa ph'enyl or alkyl-; halogen-, orjammy-substituted phenyl radical. "Iiomthe' nitrogen in the i-positionof the pipe'r'a- The bond 'ain'e'ringfmusflbeto a carbon'adjacentto anitrogen in the heterocyclic radical.

Thecompounds of thepr'esent invention being 1;4--substituted"piperaz'ines, the latter ring" is shownas saturated; However, inaddition to the "lj4' substituents; the carbon atoms of the ring mayalsobe substituted; As shownin the generic formula above, 1 1 andyz'may' be either'hydrogen or"'methyl. The invention, therefore;contemplates "lfl disubstituted' monoand (ii-methyl "piperazines;

The compounds'of'the presentinvention, therefore, may be classified'asthio-carbamyl piperazines. In generaL theyIconiprise whitecrystalline materials which are, in general, relatively insolubleiffordinal'ye'ther and petroleum ether, only slightlysoluble water, butreadily'soluble in *therordinary"alkanolsp Compounds of the presentinvention in general have anticonvulsant propertiest They exhibitdistinct possibilities as pharmaoologically active compounds for thispurpose 1 Preparationof the-new compounds of the present invention maybe accomplished in several wayanepenuent "to merge extent "on the natureof the product to be obtained. Certain methods are specific to aparticular group of compounds. However, one method is generallyapplicable to the preparation of these compounds. This method may berepresented as follows: a m 'NCSX II" Hot-N H N-'H Het H o-N- is W2 1/2(wherein Xis halogen). Whilethis'type reattion is of general utility,certainprecautionsmiist be exercis'edwith respect to its use. e V

For example, areaction ofa monoheterocyclic piperazine with athioc'arbamyl halide; asrepresented' above, is usually accompanied bythe'evolution' of heat. TheeXotheriniccharacterof the reaction maybecontrolled readily as by cooling the reaction'mixture, by regulating therateo'f mixing the two reactants, and by using afsolvent and/or diluentfor thereaction. Though a'solvent need not be used for thisreaction, weprefer to use a solvent.

Though a wide varietyof materialsj,' suchl as benzene, toluene,chlorobenzene, dib'utylether, dioxane, diethyl ether, and the like maybeus''d as solvents for the reaction, weprefer to"'use benzene.

During the course of this reacticamonofthe by-products evolved is ahydrogen halide; We prefer to 'neutralizethis asitisformed. In order toaccomplish this, an acid-binding agent, such "as an alkali metalcarbonate'or bicarbonate, or

a basic organic substance, such aspyridine, quinoline, lutidineand thelike," is 'usuallyaddedfat the start. We prefer to use a carbonateorbicarbonate;

The'temperature atwhich reaction is carried out is nut unduly critical.The temperature range usually is determined both by the nature of thereactants and the nature of'the solvent. Since, however, the reaction isexothermic, control of the temperature is'usually desirable iand may beaccomplished as previously described. In general, wherebenzene is usedas the solventgth'e reactionis preferably carried out between 10 C. andthe boiling point of benzene. H

Depending uponthe nature" of the productfit may or may notb'e soluble inthe reaction mix- 'tur. If it is soluble, the reaction"miigtureisfiltered to remove insoluble'saltsQ The filtratels concentrated. bydistillation or the bnze fi afid thep'r'oduct, which 'is' left as aresidue, is usually cyclic piperazine.

purified by crystallization from a solvent, such as water, a loweralkanol, ethyl acetate, methyl ethyl ketone, acetone, or a mixed solventsuch as alcohol-ether. The solvent chosen for this purpose is dependentupon the character of the product.

Though the above method is generally applicable, it is, due to theavailability of starting materials, particularly useful for thepreparation of 1 (di substituted thiocarbamyl) -4-heterocyclicpiperazines; while more specific methods are more useful for thepreparation of l-(monosubstituted thiocarbamyl) and l-(unsubstitutedthiocarbamyl) -4-heterocyclic piperazines.

1- (mono-substituted thiocarbamyl) -4-heterocyclic piperazines are mostreadily prepared by the reaction of a heterocyclic piperazine with anorganic isothiocyanate. This reaction may be represented as follows:

While this reaction is of general utility, certain precautions must benoted with regard to its use.

In most instances this general reaction is exothermic. However, theexothermic character of thereaction may be controlled readily by coolinthe reaction mixtures, by regulating the rate of mixing of the tworeactants, and by using a solvent and/or diluent for the reaction.Though A sol- The proper choice of a solvent is proceeds.

Though a wide variety of materials, such as petroleum ether, naphtha,benzene, toluene, ch10- robenzene, dioxane, chloroform, pyridine, andthe like, may be used as solvents for the above general reaction, adialkyl ether, such as diethyl ether, dibutyl ether and the like ispreferable. .These ether solvents are particularly eifective indissolving both of the reactants and yet allowing the product of thereaction to crystallize freely as it is formed.

In general, the temperature at which this general reaction may becarried out is not critical.

.If necessary it may be carried out between C.

and the boiling point of the solvent. However, for practical reasons,the temperature range of about 0 to 35 C. is to be preferred.

Isolation of the product from the reaction mixture is readilyaccomplished. Since the product crystallize in a relatively pure formdirectly from the reaction mixture, it may be isolated "simply byfiltration. If it is desirable to have the product in a state of higherpurity than it is after isolation, the product may be recrystallized'from a suitable solvent, such as naphtha, or a mixed solvent, such asalcohol-ether.

1- (unsubstituted thiocarbamyl) -4-heterocyclic piperazines may mostreadily be prepared by heating the thiocyanate addition salt of ahetero- This heterocyclic piperazine thiocyanate salt is convenientlyprepared by the reaction of a heterocyclic piperazine with thio- 1cyanic acid. The conversion of a heterocyclic piperazine to a1-thiocarbamyll-heterocyclic 4 plperazine may, therefore, be representedin two steps as follows:

The reaction between the heterocyclic piperazines, which, in general,are liquids miscible with water, and thiocyanic acid, an unstable gas atroom temperature, is most conveniently carried out in the presence of asolvent. While a variety of solvents may be used, water is the preferredmedium, and the reaction proceeds rapidly at room temperature. Sinceaqueous solutions of thiocyanic acid decompose on standing, freshlyprepared solutions are always used and may be obtained in several ways.The heterocyclic piperazine itself may be dissolved in an aqueoussolution together with a Water-soluble inorganic thiocyanate, such aspotassium thiocynate, ammonium thiocyanate, or the like, and thesolution acidified. Alternately, an acid addition salt of theheterocyclic piperazine such as a hydrochloride, sulfate, hydrobromideand the like may be dissolved in water and treated with a solubleinorganic thiocyanate. Anotheruseful method is the treatment of aheterocyclic piperazine solution with a freshly acidified solution of anorganic thiocyanate. The acid used is not critical; such acids ashydrochloric, hydrobromic, sulfuric, acetic and the like may be used.Since acid addition salts of heterocyclic piperazines with hydrochloricacid, sulfuric acid and the like are readily available and convenient tohandle it is preferred to use them for the preparation of thel-heterocyclicpiperazine thiocyanates. When the reaction iscarried outin the preferred solvent, water, the thiocyanate salt crystallizedirectly fromthe reaction mixture, and is isolated and dried. This saltis then heated to about its melting temperature for several hours, andthe l-(unsubstituted thiocarbamyl)- 4-heterocyclic-piperazine isisolated from the melt. The thiocarbamyl compounds are, in general, lesssoluble than the corresponding thiocyanate salts, and usually may beseparated from unreacted thiocyanate salts by recrystallization fromwater. If further purification is desired, the thiocarbamyl compound maybe recrystallized from a solvent such as a lower alkanol, isopropylacetate, or the like. 3

Preparation of compounds within the scope of this invention is morefully shown in the following examples which are given as illustrativeonly and not by way of limitation. All parts are by weight unlessotherwise noted.

EXAMPLE 1 I-(Z-p' ridyZ) -4-thiocarbamylpiperazine To a solution of 246parts of 1-(2-pyridyl),--piperazine in 300 parts of water is added 150parts of concentrated hydrochloric acid. Then a solution of 150 parts ofpotassium thiocyanate in 150 parts of water is added at roomtemperature. The 1-(2-pyridyl) -piperazine thiocyanate is isolated byfiltration and, when purified byrecrystallization from water, melt at-137 C. This salt is then fused and the melt is held at about 150 C. forseven hours to give the product, 1-(2- pyridyl)-4-thiocarbamylpiperazinewhich, when pure, melts at 171.0-171.5 C.

EXAMPLE 2 1 Z-pymeinyl -4- thz'ocarbamylpz'perazine 1- (Z-pyrz'midyl)-4-thiocarbamylpiperazine By following the same procedure as Example 1except that an equivalent amount of l-(2- pyrimidyl)-piperazine issubstituted for 1-(2- pyridyl) -piperazine, 1- (Z-pyrimidyl)-4-thiocarbamylpiperazine, melting point 178.0-178.5 0., is obtained.

EXAMPLE 4:

1- (Z-pyrz'dyl) -4-ethylthiocarbamyZ-pipemzine A solution of 26 parts ofethyl isothiocyanate in 140 parts of dry ether is slowly added withcooling, over a period of about minutes, to a solution of 50 parts of1-(2-pyridy1)-piperazine in 140 parts of dry ether. The whiteprecipitate is isolated by filtration and crystallized from benzene. Itmelts at 98-99 C.

By following the above procedure, but by substituting therein anequivalent amount of an isothiocyanate shown in column 1 of thefollowing table for the ethyl isothiocyanate and an equivalent amount ofthe corresponding l-heterocyclicpiperazine in column 2 of the table forthe I-(Z-pyridyl)-piperazine, the substituted piperazine listed oppositein column 3 is obtained. The melting point of each of the latter islisted opposite in column 4.

6 Iclaim: 1. A heterocyclic thiocarbamyl piperazine of the formula:

11] i Het-N H NCN R2 02 wherein 2/1 and ya are selected from the groupconsisting of hydrogen and. methyl, Het is a heterocyclic radicalselected from the group consisting of the pyridyl, pyrimidyl, pyrazinyland thiazolyl radicals, the bond from the nitrogen in the piperazinering to the Het radical being to a carbon adjacent to a nitrogen in saidHet radical, R1 is hydrogen and R2 is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl and phenyl radicals.

2. A thiocarbamyl piperazine having the formula:

\N/ N H N-("J-NHRr in which R1 is a lower alkenyl radical.

3. 1 (2 pyridyl)-4-allylthiocarbamylpiperazine.

4. 1 (2-pyrazinyl)-4-allylthiocarbamylpiperazine.

5. 1 azine.

6. 1 (2-pyrimidyl)-4-allylthiocarbamylpiperazine.

7. 1 azine.

(Z-thiazolyl) -4-ethylthiocarbamylpiper- (2-pyridyl)l-phenylthiocarbamylpiper- EDWARD A. CONROY.

No references cited.

1. A HETEROCYCLIC THIOCARBAMYL PIPERAZINE OF THE FORMULA: